Synthesis of indole thiazole compounds as ligands for the Ah receptor

Abstract

A method of synthesizing aromatic ketone compositions of formula I comprising the step of introducing a double bond into the 5 membered ring of the 4,5-dihydro-1,3-azoles moiety of formula II is disclosed. A method of synthesizing aromatic ketone compositions of formula I comprising the step of ring synthesis of the tetrahydro-1,3-azoles of formula XI is also disclosed.

1. A method of synthesizing aromatic ketone compositions of formula I: 
                 
 
       wherein:
 R 1  may be hydrogen or can be selected from the group consisting of (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl, and wherein the alkyl group can be substituted by (C 3 -C 7 )-cycloalkyl or can be mono- or polysubstituted by an aryl group, wherein the aryl group can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and nitro groups;  
 R 1  may be an aryl group, wherein the aryl group can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and nitro groups;  
 R 1  may further be a protecting group;  
 R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  may be the same or different and are each selected from the group consisting of hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 1 -C 6 )-acyl, (C 1 -C 6 )-alkoxy, alkoxycarbonyl (COOR 1 ), halogen, benzyloxy, the nitro group, the amino group, the (C 1 -C 4 )-mono or dialkyl-substituted amino group, or an aryl group, wherein the aryl group can be mono- or polysubstituted by halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, hydroxy and nitro groups;  
 X and Z may be the same or different and are each selected from the group consisting of O, S and NH;  
 
       comprising the step of introducing a double bond into the 5 membered ring of the 4,5-dihydro-1,3-azoles moiety of a compound of the formula II: 
                 
 
       wherein the stereochemical centers may have R or S configuration. 
     
     
       2. The method of  claim 1 , wherein the step of introducing a double bond comprises oxidation of a compound of the formula II. 
     
     
       3. The method of  claim 2 , wherein the oxidation comprises treatment of the selected compound with MnO 2  or NiO 2 . 
     
     
       4. The method of  claim 1 , wherein the compound of formula II is prepared by cyclization of the derivatives of the N-substituted indole-3-glyoxylamide of formula III: 
                 
 
       where R 8  represents hydrogen or a protecting group. 
     
     
       5. The method of  claim 4 , wherein the cyclization comprises treatment with TiCl 4 . 
     
     
       6. The method of  claim 1 , wherein the compound of formula II is prepared by cyclization of derivatives of the indole-3-glyoxylates of formula IV: 
                 
 
       where Z may be O or S, and R 8  represents hydrogen or the protecting group. 
     
     
       7. The method of  claim 4 , wherein the derivatives of the N-substituted indole-3-glyoxylamide of formula III are obtained from derivatives of indole-3-glyoxylic acid of formula V, and the corresponding amines of formula VI: 
                 
 
       where Y is selected from amino group, halogen, hydroxyl, alkoxy group (OR 1 ), mercapto group (SH) or alkylthio group (SR 1 ). 
     
     
       8. The method of  claim 6 , wherein derivatives of formula IV are obtained from the derivatives of indole-3-glyoxylic acid of formula V, and the corresponding alcohols or thiols of formula VII: 
                 
 
     
     
       9. A method of synthesizing aromatic ketone compositions of formula I comprising the step of introducing two double bonds into the 5 membered ring of the tetrahydro-1,3-azoles of formula XI: 
                 
 
     
     
       10. The method of  claim 9 , wherein the compound of formula XI is prepared from derivatives of the indole-3-glyoxals of formula X and the corresponding amines of formula VI: 
                 
 
     
     
       11. The method of  claim 1  additionally comprising the step of testing the compound for efficacy as an AHR ligand. 
     
     
       12. The method of  claim 9  additionally comprising the step of testing the compound for efficacy as an AHR ligand.